Genes and Environment in Diabetes Mellitus : A multi-species approach

糖尿病的基因和环境：多物种方法

• 批准号: MR/R007977/1
• 负责人: Lucy Jane Davison
• 金额: $ 193.28万
• 依托单位: Royal Veterinary College
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR007977%2F1
• 关键词: Genes; Environment; Diabetes; Mellitus; multi

Type 1 diabetes (T1D) affects more than 400,000 people in the UK including up to 30,000 children. Treatment involves lifelong daily insulin injections and the disease arises as the result of genetic and environmental factors, which cause the immune system to destroy the cells in the pancreas which normally produce insulin. This project is aimed at understanding more about the risk factors involved in type 1 diabetes (T1D) and in particular whether it might be possible to reduce the risk of T1D by making environmental changes.The incidence of T1D has been rising year on year since the 1950s, coinciding with more frequent use of antibiotics for childhood infections. One theory is that antibiotics disrupt the balance of micro-organism in the gut (known as the microbiome). The microbiome is known to be involved in the development of the immune system and a healthy microbiome is thought to be involved in protecting against the development of T1D. Studies of the microbiome in children affected with T1D demonstrate many differences in the type, frequency and diversity of micro-organisms compared to the microbiome of children without T1D. Mouse models of T1D such as the NOD (non-obese diabetic) mouse have also demonstrated a relationship between antibiotic use and T1D risk. In addition, recent evidence has suggested that a gene called DEXI may be involved in microbiome development, as well as T1D risk. This proposal will examine the relationship between the microbiome, the DEXI gene and T1D risk. In the NOD model, the microbiome will be examine by looking at the genetic material from micro-organisms in the faeces, throughout the life course. The effect on the microbiome of of having an functional or non-functional Dexi gene will also be explored. In addition, the impact of measures to improve microbiome health on the development of T1D on this model will also be explored.In addition, a new model for studying the microbiome and diabetes development will be explored. Pet dogs can develop spontaneous insulin-dependent diabetes mellitus just like young humans and importantly they have the advantage over the NOD model that they share our environment. This study will also use a large veterinary database to assess the impact of antibiotic use on the risk of diabetes development in pet dogs. In addition, samples of faeces will be collected from pet dogs undergoing treatment for newly diagnosed diabetes in a veterinary hospital, as well as non-diabetic dogs to determine if the same relationship between microbiome and diabetes exists in dogs as in children. Finally, the role of DEXI in the human immune system will be explored. New methods of detection of the DEXI protein in blood samples and the immune system will be developed, to allow the relationship between DEXI, the microbiome and the development of the human immune system to be explored in future.

1型糖尿病（T1D）影响英国超过40万人，其中包括多达3万名儿童。治疗包括终身每天注射胰岛素，这种疾病是由于遗传和环境因素引起的，这些因素导致免疫系统破坏胰腺中正常产生胰岛素的细胞。该项目旨在进一步了解1型糖尿病（T1D）的危险因素，特别是是否有可能通过改变环境来降低T1D的风险。自20世纪50年代以来，T1D的发病率逐年上升，与儿童感染更频繁地使用抗生素相吻合。一种理论是抗生素破坏了肠道微生物（称为微生物组）的平衡。已知微生物组参与免疫系统的发育，健康的微生物组被认为参与预防T1D的发展。对患有T1D的儿童的微生物组的研究表明，与没有T1D的儿童的微生物组相比，微生物的类型，频率和多样性存在许多差异。T1D的小鼠模型，如NOD（非肥胖糖尿病）小鼠，也证明了抗生素使用与T1D风险之间的关系。此外，最近的证据表明，一种名为DEXI的基因可能与微生物组的发育以及T1D风险有关。该提案将研究微生物组，DEXI基因和T1D风险之间的关系。在NOD模型中，将通过观察整个生命过程中粪便中微生物的遗传物质来检查微生物组。还将探索具有功能性或非功能性Dexi基因对微生物组的影响。此外，还将探索改善微生物组健康的措施对T1D发展的影响。此外，还将探索研究微生物组和糖尿病发展的新模型。宠物狗可以像年轻人一样患上自发性胰岛素依赖性糖尿病，重要的是，它们比NOD模型具有优势，因为它们与我们共享环境。这项研究还将使用一个大型兽医数据库来评估抗生素使用对宠物狗糖尿病发展风险的影响。此外，将从兽医医院接受新诊断糖尿病治疗的宠物犬以及非糖尿病犬中收集粪便样本，以确定犬中微生物组与糖尿病之间的关系是否与儿童相同。最后，将探讨DEXI在人类免疫系统中的作用。将开发检测血液样品和免疫系统中DEXI蛋白的新方法，以便将来探索DEXI、微生物组和人类免疫系统发育之间的关系。

项目成果

Dog leucocyte antigen (DLA) class II haplotypes and risk of canine diabetes mellitus in specific dog breeds.

• DOI: 10.1186/s40575-020-00093-9
• 发表时间: 2020-10-31
• 期刊: Canine medicine and genetics
• 作者: Denyer AL;Massey JP;Davison LJ;Ollier WER;Catchpole B;Kennedy LJ
• 通讯作者: Kennedy LJ

Dexi disruption depletes gut microbial metabolites and accelerates autoimmune diabetes

Dexi 破坏​​会消耗肠道微生物代谢物并加速自身免疫性糖尿病

• DOI: 10.1101/393421
• 发表时间: 2018
• 作者: Davison L

Activation of the Immune-Metabolic Receptor GPR84 Enhances Inflammation and Phagocytosis in Macrophages.

• DOI: 10.3389/fimmu.2018.01419
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Recio C;Lucy D;Purvis GSD;Iveson P;Zeboudj L;Iqbal AJ;Lin D;O'Callaghan C;Davison L;Griesbach E;Russell AJ;Wynne GM;Dib L;Monaco C;Greaves DR
• 通讯作者: Greaves DR

Diabetes mellitus in dogs attending UK primary-care practices: frequency, risk factors and survival

• DOI: 10.1186/s40575-020-00087-7
• 发表时间: 2020-06-10
• 期刊: Canine Medicine and Genetics
• 作者: Heeley AM;O’Neill DG;Davison LJ;Church DB;Corless EK;Brodbelt DC
• 通讯作者: Brodbelt DC

Insulin expression in ß cells is reduced within islets before islet loss in diabetic cats

在糖尿病猫的胰岛丧失之前，胰岛细胞内的胰岛素表达降低

• DOI: 10.17863/cam.87722
• 发表时间: 2022
• 作者: Bergomi V